Erythropoietin (EPO) is a glycoprotein hormone secreted by the kidneys in response to tissue hypoxia, which stimulates red blood cell production in the bone marrow (1). The gene for EPO has been cloned and expressed in Chinese hamster ovary cells (2,3). This recombinant human erythropoietin (epoetin alfa, rhEPO) has an amino acid sequence identical to that of human urinary erythropoietin, and the two are indistinguishable on the basis of functional and immunological assays, although differences exist regarding protein glycosylation, affecting in vivo efficacy (4,5).
In clinical trials to date, rhEPO has been evaluated in normal subjects as well as in patients with various anemic conditions (6,7). EPO induces a brisk hematologic response in normal human volunteers, provided that adequate supplies of iron are available to support increased hemoglobin synthesis (8). The majority of trials have investigated the safety and effectiveness of rhEPO in the treatment of chronic renal failure maintained on dialysis and in those not yet on maintenance dialysis. Other indications approved in the US include anemia secondary to chemotherapy treatment in cancer and anemia associated with zidovudine treatment of human immunodeficiency virus infection. Worldwide, EPO has been used to treat anemia associated with rheumatoid arthritis, prematurity, myelofibrosis, sickle cell anemia, bone marrow transplantation, thermal injury, β-thalassemia, as a facilitator of presurgical autologous blood donation, and use as a presurgical adjuvant (6,7). Although rhEPO is generally well tolerated, occasional skin rashes and urticaria have been observed suggesting allergic hypersensitivity to some components of the Epoetin alfa formulation, likely human serum albumin. Further, despite blood screening, there exists a risk of infection with a transmissible agent when a pharmaceutical agent is formulated using human blood products. Therefore pharmaceutical formulations of rhEPO that are stable and are free of human blood products, such as albumin are needed.
Epoetin alfa has been effectively and safely used to raise and maintain target hemoglobin when dosed weekly. Recent efforts have attempted to decrease dosing frequency by increasing the dose level and/or by modifying erythropoietin (EPO) to increase the serum half-life. We sought to address the following questions in a non-human primate model system. 1.) Is a target hemoglobin level achieved faster with a weekly dosing regimen as compared to high dose EPO administration given less frequently? 2.) Is rHuEPO effective at maintaining hemoglobin level with a less frequent dosing interval if initiated at an elevated hemoglobin level? A cohort of cynomolgus primates were dosed weekly, 5000 IU/kg sc until a 3–4 g/dL increase in hemoglobin was achieved. Animals were then randomized into two different EPO dose level groups (17,000 or 25,000 IU/kg) given every two or three weeks. At the time of randomization, a second cohort of primates was dosed with EPO at either 17,000 IU/kg or 25,000 IU/kg administered every two or three weeks. Animals remained in the study for 145 days with CBC analysis performed twice weekly. A 3 –4 g/dL rise in hemoglobin was observed after 28 days if EPO was given 5,000 IU/kg weekly while the same increase was observed after 50 days if given every two weeks at either 17,000 or 25,000 IU/kg. However, once the target hemoglobin level was achieved, 3 –4 g/dL above baseline, it was maintained within 1 g/dL of the target level if EPO was given every two or three weeks. We conclude that target hemoglobin was achieved faster if dosed with a weekly dosing regimen compared to increasing the dose level given less frequently. Secondly, rHuEPO is effective at maintaining target hemoglobin with a two or three week dosing regimen if initiated at elevated hemoglobin levels. Our results show that an alternate dosing regimen whereby hemoglobin is raised by a weekly dosing regimen then switched to either a once every two weeks or once every three weeks dosing regimen is an effective and safe mechanism that provides both convenience and efficacy to the patient population.